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Rewriting Life

DNA Chips

They can analyze thousands of genes at a time. Here’s how.

In the past few years, the promises of biotechnology-new knowledge of health and disease, better diagnostics and treatments-have been driven ever closer to fruition by an unprecedented torrent of biological data flowing from research labs. One of the key technologies generating this critical new wealth of information is a postage-stamp-sized slide of glass or plastic called a DNA microarray or, more colloquially, a DNA chip.

DNA chips made their big splash in 1996 when Santa Clara, Calif.-based Affymetrix introduced the first commercial version, which the company dubbed GeneChip. Affymetrix uses light-sensitive chemical reactions to grow a gridlike pattern of as many as 400,000 short DNA strands, called probes, on a glass wafer. Since each probe can bind to a different gene sequence in a sample of DNA, the chips allow researchers to perform what once would have been thousands of separate experiments all at the same time. Researchers in biotechnology, pharmaceuticals and the Human Genome Project were dazzled by the possibilities: new understanding of the role genes play in heart disease or antibiotic resistance, tools for prenatal or infection diagnosis that incorporate all the genes of interest on a single chip, massive-scale automated screening of potential drugs.

Today, dozens of companies provide DNA-chip products and services. With the development of new ways to fabricate the chips, researchers now have the option of buying ready-made chips or building their own customized chips right in the lab. And some of the earliest hopes about the technology-particularly that it would help reveal the genetic underpinnings of cancer-already show signs of fulfillment. Just last year, for example, researchers at the Stanford University School of Medicine used DNA chips to discover two genetically distinct classes of disease within a type of lymphoma previously classified as one cancer; since a patient’s chance of survival depends significantly on which of the two subtypes he or she has, understanding the differences between the two could lead to better-tailored treatments.

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To show just how DNA chips work, TR walks you though a hypothetical cancer experiment, step by step.

1) One important role for DNA chips lies in uncovering the genetic differences between similar cancers-two types of leukemia, for example. To do that, you would start with a group of patients, some of whom have one type of cancer and some of whom have another.

2) For each patient, take a sample of cancer cells and isolate all the genes that are active in those cells. Make copies of those genes, incorporating some special nucleotides, or DNA letters, that have a fluorescent dye attached to them.

3) Put the new gene copies onto a DNA microarray, a chip covered with a grid of several thousands of “probes”-short stretches of DNA that each bind to a unique gene sequence.

4) When a probe matches one of the genes that are active in the cancer cells, it binds to the copy of that gene. Once binding takes place, wash the extra free-floating DNA away.

5) Put the DNA chip into the chip scanner. There, a laser shines light on the chip and causes the fluorescent dye to glow, making a pattern of light spots where labeled gene copies are bound to probes and dark spots where there are unbound probes. The scanner detects the fluorescence and records an image of the grid of light and dark.

6) Using a computer that has been fed a map of where each probe is on the microarray, you can determine which genes are active in each sample. Careful analysis of these results can allow you to pinpoint small sets of genes that are active in one cancer but not the other. In the future, these genes could become targets for new drugs, or could be the basis for new, highly specific diagnostic tests.

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